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Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents.

Authors :
Niu Y
Wang M
Cao Y
Nimmagadda A
Hu J
Wu Y
Cai J
Ye XS
Source :
Journal of medicinal chemistry [J Med Chem] 2018 Apr 12; Vol. 61 (7), pp. 2865-2874. Date of Electronic Publication: 2018 Mar 28.
Publication Year :
2018

Abstract

Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.

Details

Language :
English
ISSN :
1520-4804
Volume :
61
Issue :
7
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
29569910
Full Text :
https://doi.org/10.1021/acs.jmedchem.7b01704